Ho et al. found that the small molecule LB-100, an inhibitor of protein phosphatase-2A (PP2A), in combination with anti-PD-1, induced CD8+ T cell-dependent tumor regression in a majority (complete response in half) of mice with established CT26 colorectal tumors, and protected complete responders from rechallenge. Mechanistically, the combination increased tumor infiltration by CD8+ T cells with enhanced effector and cytolytic functions. LB-100 also activated the mTORC1 pathway, reducing CD4+ T cell differentiation into Tregs and promoting Th1 cytokine secretion. LB-100 and anti-PD-1 prophylactically controlled B16 melanoma.
Mounting evidence suggests that inhibition of protein phosphatase-2A (PP2A), a serine/threonine phosphatase, could enhance anticancer immunity. However, drugs targeting PP2A are not currently available. Here, we report that a PP2A inhibitor, LB-100, when combined with anti-PD-1 (aPD-1) blockade can synergistically elicit a durable immune-mediated antitumor response in a murine CT26 colon cancer model. This effect is T-cell dependent, leading to regression of a significant proportion of tumors. Analysis of tumor lymphocytes demonstrates enhanced effector T-cell and reduced suppressive regulatory T-cell infiltration. Clearance of tumor establishes antigen-specific secondary protective immunity. A synergistic effect of LB-100 and aPD-1 blockade is also observed in B16 melanoma model. In addition, LB-100 activates the mTORC1 signaling pathway resulting in decreased differentiation of naive CD4 cells into regulatory T cells. There is also increased expression of Th1 and decreased expression of Th2 cytokines. These data highlight the translational potential of PP2A inhibition in combination with checkpoint inhibition.
Author Info: (1) Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA. (2) Neuro-Oncology Branch, National
Author Info: (1) Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA. (2) Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. (3) Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA. (4) Lixte Biotechnology Holdings, Inc., East Setauket, NY, 11733, USA. (5) Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. (6) Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. Department of Pathology, Zhongshan Hospital, Fudan University, 200032, Shanghai, People's Republic of China. (7) AbbVie Biotherapeutics, Redwood City, CA, 94063, USA. (8) Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA. (9) Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. (10) MedImmune, Gaithersburg, MD, 20878, USA. AbbVie Biotherapeutics, Redwood City, CA, 94063, USA. (11) Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA. zhengping.zhuang@nih.gov. Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. zhengping.zhuang@nih.gov.
